Core Insights - The study reveals that phosphorylated Toll-like receptor 3 (TLR3) translocation to the nucleus in cancer cells promotes metastasis and chemoresistance, indicating a non-classical function of innate immune sensors in cancer [3][8] - The JAK1/TLR3/PRMT5/c-Myc signaling axis may serve as a potential prognostic marker and therapeutic target to overcome chemoresistance [3][8] Group 1 - The research team utilized immunohistochemical analysis on pancreatic ductal adenocarcinoma (PDAC) and various other cancer samples to observe TLR3's nuclear translocation under chemotherapy stress [6] - In vitro experiments demonstrated that nuclear TLR3 enhances cancer cell invasiveness and proliferation while inhibiting chemotherapy-induced apoptosis [6] - Mice models with nuclear TLR3-expressing cancer cells exhibited increased liver metastasis and shortened survival, indicating a malignant phenotype [6] Group 2 - Mechanistically, JAK1 phosphorylates serine 155 (S155) of TLR3, facilitating its nuclear translocation through cooperation with importin α5 [6] - The abnormal accumulation of double-stranded RNA in the nucleus under chemotherapy stress may activate nuclear TLR3 [6] - Nuclear TLR3 recruits protein arginine methyltransferase 5 (PRMT5) and interacts with c-Myc, promoting c-Myc's symmetric dimethylation and activation of downstream tumor-promoting signaling pathways [6] Group 3 - High levels of nuclear TLR3 in clinical samples predict poor patient prognosis, characterized by shorter disease-free survival and overall survival, along with a poor response to neoadjuvant chemotherapy [8] - The findings underscore the potential of the JAK1/TLR3/PRMT5/c-Myc signaling axis as a novel target for therapeutic intervention in chemoresistant cancers [8]